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A follow-up study of patients with COVID-19 presenting with seizures

      Highlights

      • Seizures in patients with COVID-19 are often acute symptomatic (in about two-thirds).
      • Seizures may be exacerbation of a pre-existing epilepsy/functional seizures (in about one-third).
      • A complete investigation of the underlying etiology of seizures is necessary.
      • Seizure outcome is generally good.

      Abstract

      Objective

      We performed a follow-up study of patients with COVID-19 presenting with seizures.

      Methods

      All consecutive patients with seizures, who were referred to Namazee Hospital, Shiraz, Iran, with a diagnosis of COVID-19, from 10 August 2020 until 20 October 2020 were included in this longitudinal study. The clinical data were collected by the admitting physician. In a follow-up phone call to the discharged patients (after eight weeks or more), we inquired their seizure outcome.

      Results

      In total, 32 patients were studied; 28 patients were followed. Twelve patients (37.5%) presented with a single tonic-clonic seizure and nine (28.1%) had convulsive status epilepticus; one patient had functional (psychogenic) seizures. Ten patients (31.3%) had pre-existing epilepsy, eight others (25%) had pre-existing CNS problems (without epilepsy), one person (3.1%) had pre-existing functional seizures, and 13 individuals (40.1%) neither had epilepsy nor had other CNS problems. Eight patients (28.6%) reported experiencing seizure(s) after being discharged from the hospital; six of these had pre-existing epilepsy and one had pre-existing functional seizures. One patient, who had a newly developed ischemic brain infarction, reported experiencing recurrent seizures.

      Conclusion

      Seizures in patients with COVID-19 are either acute symptomatic (in about two-thirds) or an exacerbation of a pre-existing epilepsy/functional seizures (in about one-third). A thorough investigation of the underlying etiology of seizures in patients with COVID-19 is necessary. Seizure outcome in patients, who are hospitalized with COVID-19 and seizures, is generally good.

      Keywords

      1. Introduction

      Previous case series have provided evidence that seizure is rarely a presenting manifestation of COVID-19; it happens in less than 1% of these patients [
      • Keshavarzi A.
      • Janbabaei G.
      • Kheyrati L.
      • Ghavamabad L.H.
      • Asadi-Pooya A.A.
      Seizure is a rare presenting manifestation of COVID-19.
      ]. However, considering the high number of patients with COVID-19 worldwide, this may translate to thousands of patients with COVID-19 and seizures globally. Furthermore, seizure is an important and serious manifestation that may complicate the course of illness in any critically ill patient. In severely ill patients, isolated seizures may quickly escalate to generalized convulsive status epilepticus or non-convulsive status epilepticus (NCSE) which are associated with a high morbidity and mortality [
      • Ch'ang J.
      • Claassen J.
      Seizures in the critically ill.
      ]. In such circumstances, a comprehensive investigation of the etiology of the seizure should be performed immediately [
      • Asadi-Pooya A.A.
      Seizures associated with coronavirus infections.
      ]. The etiology of seizure(s) in many previously reported COVID-19 patients was most likely multifactorial, as many of them had multi-organ failure, metabolic derangements, hypoxemia, fever, etc. [
      • Asadi-Pooya A.A.
      • Simani L.
      • Shahisavandi M.
      • Barzegar Z.
      COVID-19, de novo seizures, and epilepsy: a systematic review.
      ]. However, some of the patients had specific neurological problems (e.g., encephalitis or cerebrovascular events) [
      • Lyons S.
      • O’Kelly B.
      • Woods S.
      • Rowan C.
      • Brady D.
      • Sheehan G.
      • et al.
      Seizure with CSF lymphocytosis as a presenting feature of COVID-19 in an otherwise healthy young man.
      ,
      • Moriguchi T.
      • Harii N.
      • Goto J.
      • Harada D.
      • Sugawara H.
      • Takamino J.
      • et al.
      A first case of meningitis/encephalitis associated with SARS-Coronavirus-2.
      ,
      • Klein D.E.
      • Libman R.
      • Kirsch C.
      • Arora R.
      Cerebral venous thrombosis: A typical presentation of COVID-19 in the young.
      ,
      • De Stefano P.
      • Nencha U.
      • De Stefano L.
      • Mégevand P.
      • Seeck M.
      Focal EEG changes indicating critical illness associated cerebral microbleeds in a Covid-19 patient.
      ,
      • Bolaji P.
      • Kukoyi B.
      • Ahmad N.
      • Wharton C.
      Extensive cerebral venous sinus thrombosis: a potential complication in a patient with COVID-19 disease.
      ,
      • Haddad S.
      • Tayyar R.
      • Risch L.
      • Churchill G.
      • Fares E.
      • Choe M.
      • et al.
      Encephalopathy and seizure activity in a COVID-19 well controlled HIV patient.
      ].
      New-onset seizures in patients with COVID-19 have often been considered as acute symptomatic seizures [
      • Asadi-Pooya A.A.
      Seizures associated with coronavirus infections.
      ,
      • Asadi-Pooya A.A.
      • Simani L.
      • Shahisavandi M.
      • Barzegar Z.
      COVID-19, de novo seizures, and epilepsy: a systematic review.
      ]. Patients with acute symptomatic seizures do not need long-term anti-seizure medication (ASM) therapy after the period of their acute illness (i.e., about six weeks in COVID-19 patients), unless a subsequent seizure occurs [
      • Bergey G.K.
      Management of a first seizure.
      ]. However, no study has ever followed these patients to determine their seizure outcome and whether these patients experience any further unprovoked recurrent seizures after the period of their acute illness.
      The aim of the current study was to investigate the seizure outcome in patients who were hospitalized with COVID-19 and seizures. We also investigated the etiology of seizures (as a presenting manifestation) in patients with COVID-19. These two objectives (i.e., clarifying the etiology and more importantly the seizure outcome) may add to the existing literature on this important issue.

      2. Methods

      2.1 Patients

      In this study, all consecutive patients with seizures, who were referred to and admitted at Namazee Hospital, Shiraz, Iran, with a diagnosis of COVID-19, from 10 August 2020 until 20 October 2020 were included. All the patients had a confirmed COVID-19 diagnosis by a positive result on Real-Time polymerase chain reaction testing of nasopharyngeal and oropharyngeal samples, or a probable COVID-19 diagnosis by a positive chest computerized scan (CT)/X-ray (CXR) characteristic for COVID-19 (as defined by the World Health Organization) [

      WHO-2019-nCoV-Surveillance_Case_Definition-2020.2-eng.pdf/ accessed on 25 March 2021.

      ].

      2.2 Data collection

      For any patient, who was admitted with a diagnosis of COVID-19, the following data were collected at the emergency room by the admitting physician: age, sex, and presence of fever. Other collected data were included after reviewing the patients’ medical records: Real-Time polymerase chain reaction test results, chest CT scan results, CXR results, arterial blood oxygen saturation (hypoxemia was defined as saturation below 93%), the first laboratory test results, electroencephalography (EEG), brain imaging, and cerebrospinal fluid (CSF) analyses results. Underlying chronic health problems were also collected (self-declared) [i.e., renal, liver, cardiac, or neurological, and also diabetes mellitus (DM), cancer, etc.). For the purpose of this study, pre-existing neurological problems were categorized as pre-existing epilepsy or other central nervous system (CNS) problems [e.g., pre-existing cerebrovascular accidents (CVA), multiple sclerosis (MS), Alzheimer’s disease (AD), etc.]. We arbitrarily categorized the etiology of seizures as: exacerbation of a pre-existing epilepsy (or functional seizures), new CNS insults, fever, metabolic derangements, hypoxemia, meningoencephalitis, and de novo seizures in people with or without pre-existing CNS problems. The outcome (at discharge) was recorded in the database, as dead or discharged.
      In a follow-up phone call interview to the discharged patients (after eight weeks or more), we inquired their seizure outcome (whether they have experienced unprovoked recurrent seizures), drug history, and any other enduring problems.

      2.3 Statistical analyses

      Values were presented as mean ± standard deviation (SD) for continuous variables and as number (percent) of subjects for categorical variables. This is a descriptive study.

      2.4 Standard protocol approvals, registrations, and patient consents

      Shiraz University of Medical Sciences Review Board approved this study as a minimal-risk research using the data that were collected for routine clinical practice and waived the requirement for written informed consent; however, patients orally consented to be interviewed during the phone call (approval number: 22383).

      2.5 Data availability statement

      The data are confidential and will not be shared as per the regulations of Shiraz University of Medical Sciences.

      3. Results

      3.1 General characteristics of the patients

      During the study period, 32 patients [20 (62.5%) women and 12 (37.5%) men] were hospitalized with seizure(s) and a diagnosis of COVID-19. The mean age (± standard deviation) of the patients was 22.8 (± 20.4) years (range: one month to 65 years; median: 14.5 years; interquartile range: 33 years). In total, three patients died at the hospital (case fatality rate = 9.4%); these were not included in the follow-up phase of the study. One other patient did not answer the phone calls and was not included in the follow-up phase of the study. Table 1 shows all the details of the studied patients.
      Table 1Characteristics of the studied patients.
      AgeSexSeizure typePre-existing ComorbidityFeverHypoxemiaBrain imagingEEGCSF analysesPresumed seizure etiologyFollow-up duration, daysFollow-up seizureCOVID-19 diagnosis
      10.1FFocal clonicNoneNoNo1Right temporal spikes0Hypocalcemia (Ca: 5.5 mg/dL)57No2
      20.5MTCEpilepsyYesNo0C3, P3, C4 sharp waves0Exacerbation, fever58No3
      31.0FTCNoneYesYes2, HydrocephalusNormal2Encephalitis57No3
      41.3FFSNoneYesNo0NA0Fever81No2
      52.0FTCCerebral palsyYesNo2, Hypoxic brain damageNormal1Fever, pre-existing condition-No response3
      62.0FFSNoneYesNo1Normal1Fever110No3
      73.0MTCEpilepsyYesNo0NA0Exacerbation, fever56Yes3
      83.5FTonicLiver and kidney diseaseYesNo1F3, F4 sharp waves0Fever, pre-existing condition101No1
      94.0MSEEpilepsyYesYes1Normal1Exacerbation, fever, hypoxemia57Yes3
      105.5FFSNoneYesNo1Normal0Fever71No3
      117.0FTonicNoneNoYes1NCSE: Spike-waves (1.5 Hz, more than 90% of the recording)0Hypoxemia77No2
      128.5FSEEpilepsyYesYes2, HydrocephalusNormal0Exacerbation, fever, hypoxemia-Expired3
      1310.0FTCEpilepsyNoNo2, TORCHNA0Exacerbation61No1
      1411.0FTonicNoneYesyes3, recent CVANA0CVA, fever, hypoxemia, BUN: 33 mg/dL94Yes3
      1511.0FSECerebral palsyNoNo1NA0Pre-existing condition57No2
      1612.0FTCNoneYesNo0Slow background, multifocal spike-waves0Fever79No1
      1717.0MTCHeart diseaseYesYes3, recent CVANA0CVA, fever, hypoxemia125No3
      1826.0FTCEpilepsyYesNo1Normal0Exacerbation, fever75No2
      1926.5MSENoneNoNo1NA0Unknown111No2
      2032.0MSEBrain tumorYesYes2, TumorSlow background1Fever, pre-existing condition75No1
      2135.0FSerialNoneYesYes2, Old ischemic changesSlow background, generalized frontally dominant spike-waves0Fever, hypoxemia, pre-existing condition127No2
      2236.0MFunctionalFunctional seizuresNoNo1Functional seizure0Exacerbation89Yes1
      2336.0MSerialEpilepsyYesNo1Normal0Exacerbation, fever, hypoglycemia (BS: 48 mg/dL)74Yes2
      2436.0FSEDiabetes mellitusYesYes3, CVTNA0CVT, fever, hypoxemia90No2
      2537.0FSerialBrain tumorNoYes2, TumorSlow background, right hemisphere polymorphic delta activity0Hypoxemia, pre-existing condition88No1
      2639.0MTCEpilepsyYesYes1NA0Exacerbation, fever, hypoxemia118Yes2
      2745.0MSEOld CVAYesYes2, Old CVANormal0Fever, hypoxemia, hypernatremia (Na: 153 mEq/L), pre-existing condition110No2
      2849.0MSEOld CVANoYes2, Old CVANormal0Hypoxemia, pre-existing conditionExpired2
      2951.0FTCNoneNoYes1Left temporal spikes0Hypoxemia121No2
      3059.0FTCBrain tumorYesYes2, TumorSlow background0Fever, hypoxemia, pre-existing condition-Expired2
      3160.0FSEEpilepsyNoYes2, Old ischemic changesSlow background0Exacerbation, hypoxemia103Yes2
      3265.0MTCEpilepsyNoYes2, Old ischemic changesSlow background, T5 sharp waves0Exacerbation, hypoxemia111Yes2
      Age: years; F: female; M: male; TC: tonic-clonic; FS: febrile seizure; SE: status epilepticus; Imaging (No: 0; Normal: 1; Chronic and pre-existing abnormality: 2; Acute problem: 3); CSF: cerebrospinal fluid; CSF analyses (none: 0; Normal: 1; Abnormal: 2); EEG: electroencephalography; NCSE: Non-convulsive status epilepticus; COVID-19 diagnosis (PCR: 1; CT scan: 2; CXR: 3); BUN: blood urea nitrogen; CVA: cerebrovascular accident; CVT: cerebral venous thrombosis; BS: blood sugar; Na: sodium level; Ca: Calcium level; TORCH: Congenital infection with toxoplasmosis, rubella, cytomegalovirus, herpes simplex, and other organisms; NA: not available.

      3.2 Clinical presentations and characteristics

      Twelve patients (37.5%) presented with a single tonic-clonic seizure, nine (28.1%) had convulsive status epilepticus (based on the reported length of seizures and without EEG confirmation), three (children) (9.4%) had febrile seizures, three (9.4%) presented with serial tonic-clonic seizures, three (9.4%) had tonic seizures, one had a focal clonic seizure, and one patient had functional (psychogenic) seizures (documented by ictal recording during video-EEG monitoring). Ten patients (31.3%) had pre-existing epilepsy, eight others (25%) had pre-existing CNS problems (without epilepsy), one person (3.1%) had pre-existing functional seizures, and 13 individuals (40.1%) neither had epilepsy nor had other CNS problems. Among 13 patients without any pre-existing CNS problems the presenting seizures were as follows: tonic-clonic (4), tonic (3), febrile seizure (3), status epilepticus (2), focal clonic (1).

      3.3 The presumed etiology of seizures

      All patients had available data on their body temperature (at admission), arterial blood oxygen saturation, and routine laboratory test results (i.e., blood sugar and electrolytes). Twenty-eight patients had available brain imaging and five patients had CSF analyses data. Eleven patients (34.4%) had exacerbation of their pre-existing seizures; among these, seven patients had fever and six had hypoxemia. Among eight patients with pre-existing CNS problems (without epilepsy) (3 with tumors, 2 with old CVA, one with old ischemic (vascular) changes, one with hypoxic brain damage at birth, and one with cerebral palsy and normal brain imaging), five had fever and six had hypoxemia. Two patients had newly developed ischemic brain infarctions (CVA) and one other had cerebral sinus venous thrombosis (CVT). One patient had encephalitis [CSF pleocytosis (white blood cell count: 550 – lymphocyte: 97% – polymorphonuclear leukocytes: 3%); PCR (for COVID-19 or other viruses) was not performed]. Three children had febrile seizures (that is not directly related to COVID 19). Twenty patients (62.5%) had more than one presumed etiology for their seizures. Six of patients with status epilepticus/clusters (50%) and two of those with isolated seizures (10%) had pre-existing CNS problems (without epilepsy) (p = 0.023).

      3.4 Electroencephalography

      Electroencephalography was available in 23 patients. Ten patients had normal EEGs and one had documented functional seizures (on video-EEG monitoring). Among 21 patients without pre-existing seizures, 15 people had EEGs; it was normal in six patients, three patients had normal background with focal interictal epileptiform discharges, and five patients had abnormally slow background (two with interictal epileptiform discharges). One patient had NCSE.

      3.5 Outcome

      Twelve patients had either status epilepticus (N = 9) or clusters of seizures (N = 3); two of these died and three reported recurrent seizures after being discharged. Twenty patients had isolated seizures; one of them died (p = 0.540) and five others reported recurrent seizures after being discharged (p = 0.852). Twenty-eight patients were interviewed after being discharged from the hospital. The mean duration of their follow-up was 87 (±23) days (range: 56–127 days; median: 85 days; interquartile range: 47). Eight patients (28.6%) reported experiencing seizure(s) after being discharged from the hospital; six of these had pre-existing epilepsy and one had pre-existing functional seizures. One patient, who had a newly developed ischemic brain infarction (CVA), also reported experiencing seizures. From 20 patients, who did not have follow-up seizures, three had pre-existing epilepsy; among the remaining 17 patients (neither with pre-existing seizures nor with follow-up seizures), 10 patients (58.8%) were still taking daily ASMs. Eighteen patients did not report any enduring problems; 10 others (35.7%) reported enduring problems after being discharged from the hospital [three had respiratory difficulties, two reported occasional chest pain, two had headache, two had right sided paresis, and one adult patient had urinary incontinence (he also had glioblastoma multiforme)].

      3.6 Children vs. adults

      In a separate analysis, we categorized the patients according to their age (children: ≤16 years and adults ≥17 years). There were 16 patients in each group. Nine adult patients (56%) and 3 children (19%) had status epilepticus/clusters (p = 0.066). One child and two adults died (p > 0.99). Three children (19%) and five adults (31%) reported experiencing seizure(s) after being discharged from the hospital (p = 0.705).

      4. Discussion

      In the current study, we observed that seizures (as a presenting manifestation) in patients with COVID-19 are either acute symptomatic seizures (62.5%) or exacerbation of a pre-existing epilepsy/functional seizures (34.4%); only rarely a seizure heralds the beginning of an epileptic process (3.1%). Furthermore, a recent study showed that while seizures and status epilepticus could be encountered in patients with COVID-19, their occurrence did not correlate with the patients' functional outcome [
      • Danoun O.A.
      • Zillgitt A.
      • Hill C.
      • Zutshi D.
      • Harris D.
      • Osman G.
      • et al.
      Outcomes of seizures, status epilepticus, and EEG findings in critically ill patient with COVID-19.
      ]. Our observation is consistent with that in previous studies [
      • Asadi-Pooya A.A.
      • Simani L.
      • Shahisavandi M.
      • Barzegar Z.
      COVID-19, de novo seizures, and epilepsy: a systematic review.
      ,
      • Emami A.
      • Fadakar N.
      • Akbari A.
      • Lotfi M.
      • Farazdaghi M.
      • Javanmardi F.
      • et al.
      Seizure in patients with COVID-19.
      ] and it has important clinical implications. First, a thorough investigation of the underlying etiology of the seizure should be performed immediately and an appropriate treatment strategy should be implemented to resolve that cause and to prevent further escalation of seizures. Our observation that more patients with status epilepticus/clusters had pre-existing CNS problems (without epilepsy) than those with isolated seizures is important and the treating physician should pay more immediate attention to patients with COVID-19 who have any pre-existing CNS problems. Also, as with other acute symptomatic seizures, there is no need for long-term ASM therapy in patients with COVID-19 and seizure, after the period of the acute illness, unless a subsequent seizure happens. Since the period from the onset of COVID-19 symptoms to death may range from 6 days to 6 weeks, it is reasonable to continue the ASM for about 6 weeks and then tapper and discontinue the drug rapidly in 1–2 weeks [
      • Asadi-Pooya A.A.
      Seizures associated with coronavirus infections.
      ]. In spite of this, we observed that many patients continued to take their ASM(s) for longer times. It is necessary to educate the treating healthcare professionals to limit the use of unnecessary ASMs and to avoid their many adverse effects.
      In rare instances, seizures in patients with COVID-19 could be attributed to specific CNS pathologies; one of our patients had encephalitis and three others had cerebrovascular events. Neurotropic and neuro-invasive capabilities of coronaviruses have been described before. Severe acute respiratory syndrome (SARS)-coronavirus-2 (SARS-CoV2) RNA was detected in the CSF in a few patients before [
      • Moriguchi T.
      • Harii N.
      • Goto J.
      • Harada D.
      • Sugawara H.
      • Takamino J.
      • et al.
      A first case of meningitis/encephalitis associated with SARS-Coronavirus-2.
      ,
      • Haddad S.
      • Tayyar R.
      • Risch L.
      • Churchill G.
      • Fares E.
      • Choe M.
      • et al.
      Encephalopathy and seizure activity in a COVID-19 well controlled HIV patient.
      ]; however, many other studies that tested for this had negative results [
      • Asadi-Pooya A.A.
      • Simani L.
      • Shahisavandi M.
      • Barzegar Z.
      COVID-19, de novo seizures, and epilepsy: a systematic review.
      ]. Furthermore, a recent systematic review revealed a pooled incidence of 1.7% for ischemic CVA in the setting of COVID-19 infection [
      • Parsay S.
      • Vosoughi A.
      • Khabbaz A.
      • Sadigh-Eteghad S.
      The incidence and mortality ratio of ischemic cerebrovascular accidents in COVID-19 cases: a systematic review and meta-analysis.
      ]. Another systematic review concluded that cerebral venous thrombosis in the context of COVID-19 is rare, but there seems to be an increased relative risk of the condition [

      Baldini T, Asioli GM, Romoli M, Carvalho Dias M, Schulte EC, Hauer L, et al. Cerebral venous thrombosis and severe acute respiratory syndrome coronavirus-2 infection: A systematic review and meta-analysis. Eur J Neurol, 2021. doi:10.1111/ene.14727. Online ahead of print.

      ]. In any patient with COVID-19 and seizures it is necessary to request a brain imaging study, as soon as possible, to detect any potentially life-threatening condition such as CVT. It is also desirable to have CSF analyses of patients with COVID-19 and seizures; however, how a diagnosis of encephalitis might change the disease course and also the management plan in these patients should be investigated and clarified in future studies.
      In a recent study, we observed that patients with epilepsy were not susceptible to contracting COVID-19 more than that in other individuals. Furthermore, COVID-19 in patients with epilepsy was not associated with a poorer prognosis [
      • Asadi‐Pooya A.A.
      • Emami A.
      • Akbari A.
      • Javanmardi F.
      COVID-19 presentations and outcome in patients with epilepsy.
      ]. In the current study, the seizure outcome in patients, who were hospitalized with COVID-19 and seizures, were generally good. Only rarely the presenting seizure may herald the development of epilepsy in the future (in one patient with CVA in the current study). However, patients with epilepsy, who contract COVID-19, may experience an exacerbation of their seizures for a variety of reasons (e.g., fever, hypoxemia, etc.). It may be necessary to order a Real-Time polymerase chain reaction testing of nasopharyngeal and oropharyngeal samples for COVID-19 in any patient who comes to the emergency department with pre-existing epilepsy and seizure exacerbation during this pandemic.

      5. Limitations

      This was a single center study with a small sample size. We acknowledge that subtle, non-convulsive seizures, in patients presenting with alteration of mental status, may have been missed without EEG monitoring. Another limitation was the nature of the follow-up (self-reported outcome); some patients might have missed minor seizures or even severe unwitnessed seizures. Finally, the length of the follow-up was short.

      6. Conclusion

      Seizures (as a presenting manifestation) in patients with COVID-19 are either acute symptomatic seizures (in about two-thirds) or an exacerbation of a pre-existing epilepsy/functional seizures (in about one-third). A complete investigation of the underlying etiology of the seizure in patients with COVID-19 is necessary. Seizure outcome in patients, who are hospitalized with COVID-19 and seizures, is generally good and COVID-19 does not add to the risk of developing epilepsy in the future unless a significant brain insult (e.g., CVA) happens.

      7. Declarations

      Acknowledgments: Shiraz University of Medical Sciences supported this study.
      Role of the funding source: Shiraz University of Medical Sciences had no role in the study design, analysis, and interpretation of data, in the writing of the report, and in the decision to submit the paper for publication.
      Author Contributions: Ali A. Asadi-Pooya, M.D.: Designed and conceptualized the study; analyzed the data; drafted and revised the manuscript.
      Others: Data collection and revision of the manuscript.
      Availability of data and material: The data used in this study are confidential and will not be shared.
      Conflict of Interest Disclosures: Ali A. Asadi-Pooya, M.D.: Honoraria from Cobel Daruo, RaymandRad, Sanofi, and Tekaje; Royalty: Oxford University Press (Book publication). Others: none.

      Appendix A. Supplementary data

      The following are the Supplementary data to this article:

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